CA2860008C - Tetraaza-cyclopenta[a]indenyl and their use as positive allosteric modulators - Google Patents
Tetraaza-cyclopenta[a]indenyl and their use as positive allosteric modulators Download PDFInfo
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- CA2860008C CA2860008C CA2860008A CA2860008A CA2860008C CA 2860008 C CA2860008 C CA 2860008C CA 2860008 A CA2860008 A CA 2860008A CA 2860008 A CA2860008 A CA 2860008A CA 2860008 C CA2860008 C CA 2860008C
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- title compound
- tetraaza
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- 230000003281 allosteric effect Effects 0.000 title abstract description 8
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 title description 5
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 552
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims description 293
- 239000000203 mixture Substances 0.000 claims description 203
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000004480 active ingredient Substances 0.000 claims description 18
- 239000012453 solvate Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 208000015114 central nervous system disease Diseases 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 239000007821 HATU Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 201000000980 schizophrenia Diseases 0.000 claims description 6
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 208000026139 Memory disease Diseases 0.000 claims description 4
- 208000016285 Movement disease Diseases 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- 208000018737 Parkinson disease Diseases 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 3
- 125000002950 monocyclic group Chemical group 0.000 claims description 3
- 208000004296 neuralgia Diseases 0.000 claims description 3
- 208000021722 neuropathic pain Diseases 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000001845 4 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 208000000094 Chronic Pain Diseases 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims 3
- 201000010099 disease Diseases 0.000 abstract description 7
- 230000001404 mediated effect Effects 0.000 abstract description 3
- 230000003551 muscarinic effect Effects 0.000 abstract description 3
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- 239000000543 intermediate Substances 0.000 description 234
- 239000000243 solution Substances 0.000 description 223
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 218
- 238000000746 purification Methods 0.000 description 203
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 112
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 109
- 235000019341 magnesium sulphate Nutrition 0.000 description 109
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 92
- 238000004440 column chromatography Methods 0.000 description 86
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 85
- 238000005481 NMR spectroscopy Methods 0.000 description 84
- -1 hexafluorophosphate methanaminium Chemical compound 0.000 description 75
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 74
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 59
- 238000002953 preparative HPLC Methods 0.000 description 53
- 238000010626 work up procedure Methods 0.000 description 50
- 239000003921 oil Substances 0.000 description 49
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- 238000002425 crystallisation Methods 0.000 description 47
- 230000008025 crystallization Effects 0.000 description 47
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- 239000012267 brine Substances 0.000 description 46
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 46
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 238000003818 flash chromatography Methods 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 32
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- 239000000377 silicon dioxide Substances 0.000 description 29
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- 239000000725 suspension Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
- 229910052938 sodium sulfate Inorganic materials 0.000 description 26
- 235000011152 sodium sulphate Nutrition 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
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- FQFILJKFZCVHNH-UHFFFAOYSA-N tert-butyl n-[3-[(5-bromo-2-chloropyrimidin-4-yl)amino]propyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCCNC1=NC(Cl)=NC=C1Br FQFILJKFZCVHNH-UHFFFAOYSA-N 0.000 description 19
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- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 18
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 16
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Psychiatry (AREA)
- Psychology (AREA)
- Anesthesiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161578931P | 2011-12-22 | 2011-12-22 | |
| EP11195214.9 | 2011-12-22 | ||
| EP11195214.9A EP2607364A1 (en) | 2011-12-22 | 2011-12-22 | Tetraaza-cyclopenta[a]indenyl and their use as positive allosteric modulators |
| US61/578,931 | 2011-12-22 | ||
| US201261657978P | 2012-06-11 | 2012-06-11 | |
| EP12171415.8A EP2674434A1 (en) | 2012-06-11 | 2012-06-11 | Tetraaza-cyclopenta[a]indenyl and their use as positive allosteric modulators |
| US61/657,978 | 2012-06-11 | ||
| EP12171415.8 | 2012-06-11 | ||
| PCT/EP2012/004968 WO2013091773A1 (en) | 2011-12-22 | 2012-11-30 | Tetraaza-cyclopenta[a]indenyl and their use as positive allosteric modulators |
Publications (2)
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| CA2860008C true CA2860008C (en) | 2020-11-10 |
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| EP2813505A1 (en) * | 2013-06-14 | 2014-12-17 | Asceneuron SA | Tetraaza-cyclopenta[a]indenyl derivatives |
| GB201317363D0 (en) | 2013-10-01 | 2013-11-13 | Eisai Ltd | Novel compounds |
| US9844549B2 (en) | 2014-08-26 | 2017-12-19 | Astellas Pharma Inc. | 2-aminothiazole derivative or salt thereof |
| UA123262C2 (uk) * | 2015-02-11 | 2021-03-10 | Суновіон Фармасьютикалз Інк. | ЗШИТІ ДИГІДРО-4H-ПІРАЗОЛО[5,1-c][1,4]ОКСАЗИНІЛОВІ СПОЛУКИ І АНАЛОГИ ДЛЯ ЛІКУВАННЯ ЗАХВОРЮВАНЬ ЦНС |
| WO2017038650A1 (ja) * | 2015-08-28 | 2017-03-09 | 積水メディカル株式会社 | ベンジル化合物 |
| EA201990399A1 (ru) | 2016-07-29 | 2019-07-31 | Суновион Фармасьютикалз, Инк. | Соединения, композиции и их применение |
| CN111183138A (zh) | 2017-08-02 | 2020-05-19 | 赛诺维信制药公司 | 异色满化合物以及用途 |
| BR112020012197A2 (pt) | 2017-12-21 | 2020-11-24 | Ribon Therapeutics Inc. | quinazolinonas como inibidores de parp14 |
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| CA2441926A1 (en) * | 2001-03-27 | 2002-10-03 | Neurogen Corporation | (oxo-pyrazolo[1,5a]pyrimidin-2-yl)alkyl-carboxamides |
| MX2007006896A (es) * | 2004-12-15 | 2007-06-26 | Hoffmann La Roche | Fenil-metanonas bi- y triciclicas sustituidas como inhibidores del transportador 1 de glicina (glyt-1) para el tratamiento de la enfermedad de alzheimer. |
| JP5232160B2 (ja) * | 2006-11-14 | 2013-07-10 | メルク・シャープ・アンド・ドーム・コーポレーション | 糖尿病の治療又は予防のためのジペプチジルペプチダーゼivインヒビターとしての三環式芳香族複素環化合物 |
| WO2011137049A1 (en) * | 2010-04-30 | 2011-11-03 | Merck Sharp & Dohme Corp. | Heterocyclic quinolizine derived m1 receptor positive allosteric modulators |
| EP2813505A1 (en) * | 2013-06-14 | 2014-12-17 | Asceneuron SA | Tetraaza-cyclopenta[a]indenyl derivatives |
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| US9403835B2 (en) | 2016-08-02 |
| CN104039789A (zh) | 2014-09-10 |
| EP2794608B1 (en) | 2016-09-14 |
| US20150018343A1 (en) | 2015-01-15 |
| AU2012357169A1 (en) | 2014-08-07 |
| JP2015502371A (ja) | 2015-01-22 |
| AU2012357169B2 (en) | 2017-03-30 |
| CN104039789B (zh) | 2016-09-07 |
| WO2013091773A1 (en) | 2013-06-27 |
| EP2794608A1 (en) | 2014-10-29 |
| CA2860008A1 (en) | 2013-06-27 |
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